Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCO>[ClH:1].[CH3:8][C:6]1[NH:5][C:4]2[C:3]([N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:9]=2)=[C:2]([NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:7]=1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: Nc1ccccc1
Solvent: CCO
Product: Cc1nc(Nc2ccccc2)c2nc(-c3ccccc3)cc-2[nH]1
Product: Cl
Temperature: 25 °C
Yield: 82.6 %

Procedure:
To a 5-mL, wheaton vial were added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1 (e)) (100 mg, 0.41 mmol) and aniline (Aldrich Chemical Company) (0.37 mL, 4.1 mmol), followed by EtOH (1.5 mL). The reaction was heated at reflux for 4 h. The reaction mixture was allowed to cool to room temperature and the precipitate was collected by filtration, washed with hexanes, dried in a vacuum oven overnight to give 114 mg of a brown solid. The material was recrystallized from EtOH to give 57 mg (41%) of the title compound as an off-white solid. 1H NMR (DMSO-d6; 400 MHz): d 2.67 (s, 3), 7.04 (s, 1), 7.21-7.23 (m, 1), 7.44-7.59 (m, 5), 8.03 (d, 2, J=8.0), 8.15 (d, 2, J=8.0), 11.61 (br s, 1), 13.84 (br s, 1). MS m/z: 301 (M+1).
Reaction SMILES: [CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([C:24]([N:26]2[CH2:30][CH2:29][N:28]([CH3:31])[C:27]2=[O:32])=O)[CH2:7]1)(=[O:4])=[O:3].CO>O1CCCC1.C(OCC)(=O)C>[CH3:1][S:2]([O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)=[O:12])[C@H:8]([CH2:24][N:26]2[CH2:30][CH2:29][N:28]([CH3:31])[C:27]2=[O:32])[CH2:7]1)(=[O:4])=[O:3]
Reactant: CN1CCN(C(=O)[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCN(C[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48.6 %

Procedure:
To a solution of (2S,4R)-4-methanesulfonyloxy-2-(3-methyl-2-oxoimidazolidin-1-yl)carbonyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.70 g) in tetrahydrofuran (3.5 ml) was added 1.0M solution of borane-tetrahydrofuran complex in tetrahydrofuran (20.9 ml) and the mixture was stirred at ambient temperature for 1 hour and at 35°-40° C. for 2.5 hours. Methanol (20 ml) was added dropwise to the reaction mixture on ice-bath and the mixture was evaporated in vacuo. The resulting residue was dissolved in a mixture of methanol (20 ml) and 1.7M solution of hydrogen chloride in methanol (1 ml) and the mixture was allowed to stand overnight. The reaction mixture was evaporated in vacuo to give a residue. The residue was dissolved in ethyl acetate (60 ml) and the solution was washed with saturated aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (30 g) eluting with a mixture of chloroform and methanol (9:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-(3-methyl-2-oxoimidazolidin-1-yl)methyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.33 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][C@@H:11]2[CH2:13][C@@H:12]2[CH:14]2[CH2:19][CH2:18][N:17]([C:20]3[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[CH:5]=[C:4]([F:29])[C:3]=1[CH2:30][C:31]([OH:33])=O.[NH:34]1[CH2:37][CH2:36][CH2:35]1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:34]1([C:31](=[O:33])[CH2:30][C:3]2[C:2]([F:1])=[CH:7][C:6]([O:8][CH2:9][CH2:10][C@@H:11]3[CH2:13][C@@H:12]3[CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][C:23]([CH2:26][O:27][CH3:28])=[CH:22][N:21]=4)[CH2:16][CH2:15]3)=[CH:5][C:4]=2[F:29])[CH2:37][CH2:36][CH2:35]1
Reactant: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)O)c(F)c3)CC2)nc1
Reactant: C1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3cc(F)c(CC(=O)N4CCC4)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of {2,6-difluoro-4-[2-((1S,2R)-2-{1-[5-(methoxymethyl)pyrimidin-2-yl]piperidin-4-yl}cyclopropyl)ethoxy}phenyl]acetic acid (5.00 g, 10.8 mmol) in 8 ml anhydrous DMF at RT was added azetidine (0.928 g, 16.3 mmol) and N,N-diisopropylethylamine (3.78 ml, 21.7 mmol). o-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (6.18 g, 16.3 mmol) was added to the solution and the mixture stirred at RT for 4 hrs. The residue was purified by preparative biotage reverse phase (C-18) (100 g column), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%). The solid was purified by column chromatography on silica gel (Biotage 40M), eluting with EtOAc/hexanes (30% to 90%). The product was further purified by preparative biotage Reverse phase (C-18)(100 g), eluting with Acetonitrile/Water+0.1% formic acid (35% to 90%) to give the title compound. 1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 2H), 6.67 (d, J=9.4 Hz, 2H), 4.67 (t, J=13.9 Hz, 2H), 4.18 (m, 4H), 4.06 (m, 211), 3.85 (t, J=7.8 Hz, 2H), 3.38 (s, 2H), 3.23 (s, 3H), 2.85 (m, 2H), 2.20 (m, 211), 2.03 (m, 1H), 1.75 (t, J=14.2 Hz, 2H), 1.51 (m, 114), 1.21-1.25 (m, 3H), 0.87 (m, 1H), 0.57 (m, 2H), −0.08 (m, 1H). LC/MS (m/z): 501.4 (M+H)+. GPR119 Human EC50: 0.18 nM
Reaction SMILES: [F:1][CH:2](P(=O)(C1C=CC=CC=1)C1C=CC=CC=1)[F:3].C([N-]C(C)C)(C)C.[Li+].[O:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1[O:32][C:33]1[CH:50]=[CH:49][C:48]2[C@@H:47]3[C:38]([C@H:39]4[C@@:43]([CH2:45][CH2:46]3)([CH3:44])[C:42](=O)[CH2:41][CH2:40]4)=[CH:37][CH2:36][C:35]=2[CH:34]=1>O1CCCC1.C(OCC)(=O)C.O>[F:1][C:2]([F:3])=[C:42]1[CH2:41][CH2:40][C@H:39]2[C:38]3[C@H:47]([CH2:46][CH2:45][C@:43]12[CH3:44])[C:48]1[CH:35]=[CH:34][C:33]([O:32][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][O:26]2)=[CH:50][C:49]=1[CH2:36][CH:37]=3
Reactant: O=P(c1ccccc1)(c1ccccc1)C(F)F
Reactant: C[C@]12CC[C@H]3C(=CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@]12CC[C@H]3C(=CCc4cc(OC5CCCCO5)ccc43)[C@@H]1CCC2=C(F)F
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A solution of 3 g of difluoromethyldiphenylphosphine oxide in 85 ml of tetrahydrofuran is slowly mixed with 6 ml of 2 M lithium diisopropylamide solution at a bath temperature of -50° C., and it is stirred for 1 hour. Then, a solution of 1.7 g of 3-tetrahydropyranyloxy-estra-1,3,5(10),7-tetraen-17-one in 42 ml of tetrahydrofuran is slowly added, stirred for 15 minutes, slowly heated at a bath temperature of from -50° C. to 100° C. and refluxed for 2.5 hours. For working-up, it is diluted with ethyl acetate and water, suctioned off on Celite, rewashed with ethyl acetate, washed with water as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/ethyl acetate/triethylamine. 1.0 g of 17-difluoromethylene-3-tetrahydropyranyloxy-estra-1,3,5(10),7-tetraene is obtained as colorless crystals with a melting point of 83-84° C., [α]D22 =+139.6° (c=0.5% in pyridine).
Reaction SMILES: [CH3:1][S:2]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3=[CH:14][C:15]([C:17]([OH:19])=O)=[N:16][N:8]3[C:7](=[O:20])[C:6]=2[CH:5]=1)=[O:3].CN(C=O)C.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:39][C:40]1[NH:44][N:43]=[N:42][N:41]=1>N1C=CC=CC=1>[CH3:1][S:2]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][C:9]3=[CH:14][C:15]([C:17]([NH:39][C:40]4[NH:44][N:43]=[N:42][N:41]=4)=[O:19])=[N:16][N:8]3[C:7](=[O:20])[C:6]=2[CH:5]=1)=[O:3]
Reactant: CS(=O)c1ccc2[nH]c3cc(C(=O)O)nn3c(=O)c2c1
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CS(=O)c1ccc2[nH]c3cc(C(=O)Nc4nnn[nH]4)nn3c(=O)c2c1

Procedure:
From 4,9-dihydro-7-(methylsulfinyl)-9-oxo-pyrazolo-[5,1-b]quinazoline-2-carboxylic acid (1.40 g; 5 mmole), DMF (50 ml), 1,1'-carbonyl-diimidazole (2.43 g; is mmole) and 5-amino-1-H-tetrazole, monohydrate (0.62 g; 6 mmole), following the procedure of Example 3, there is obtained 4,9-dihydro-7-(methylsulfinyl)-9-oxo-N-1H-tetrazol-5-yl-pyrazolo[5,1-b]quinazoline-2-carboxamide with pyridine (4:3), mp>350°; after crystallization from pyridine-ether.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[CH:4][C:3]=1[O:20][CH3:21].[C:22]([O:27][CH2:28][CH:29]1[O:31][CH2:30]1)(=[O:26])[C:23]([CH3:25])=[CH2:24].O>CN(C)C(=O)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:21][O:20][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:6]=[CH:7][C:2]=1[O:1][CH2:30][CH:29]([OH:31])[CH2:28][O:27][C:22](=[O:26])[C:23]([CH3:25])=[CH2:24]
Reactant: C=C(C)C(=O)OCC1CO1
Reactant: COc1cc(C=Cc2ccc3ccccc3n2)ccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=C(C)C(=O)OCC(O)COc1ccc(C=Cc2ccc3ccccc3n2)cc1OC
Yield: 50 %

Procedure:
In 5 cm3 of N,N-dimethylacetamide, 2.77 g of the produced quinoline derivative was dissolved and 1.42 g of glycidyl methacrylate and 0.10 g of tetrabutylammonium chloride were added thereto. The resultant mixture was reacted by maintaining it at 90° to 100° C. for 5 hours. The reaction product was mixed with water. The oily substance separated consequently was extracted via ethyl acetate, washed thoroughly with water, and dried. The dry product was distilled to expel the solvent and then separated and purified by silica gel chromatography, to afford 2-{2-[3-methoxy-4-(2-hydroxy-3-methacryloyloxypropyloxy)-phenyl]-ethenyl}-quinoline in a yield of 50%. When this product was recrystallized via ethyl acetatehexane, there was obtained a pure product having a melting point of 119° C. It was identified by elementary analysis and infrared absorption spectrometry.
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][CH2:10]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]=2[N:22]=1.C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[NH2:12][C:13]1[S:14][C:15]2[CH2:16][CH2:17][N:18]([CH2:10][CH2:9][CH:8]=[CH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:19][CH2:20][C:21]=2[N:22]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: BrCCC=Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: Nc1nc2c(s1)CCN(CCC=Cc1ccccc1)CC2
Yield: 39 %

Procedure:
Prepared analogously to Example 8 from 4-phenyl-3-buten-1-yl-bromide [boiling point 93° C./1,5 torr; prepared from 1-cyclopropyl-1-phenyl-carbinol with phosphorous tribromide] with 4 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in pure chloroform during 8 hours at 60° C. Yield: 39% of theory, Melting point: 157°-158° C. (chloroform/toluene)
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[S:54]1[C:58]([C:59]2[CH:67]=[CH:66][C:62]([C:63](O)=[O:64])=[CH:61][CH:60]=2)=[CH:57][N:56]=[CH:55]1>CN(C=O)C.O>[O:14]=[C:13]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]1)[CH2:12][NH:11][C:63](=[O:64])[C:62]1[CH:61]=[CH:60][C:59]([C:58]2[S:54][CH:55]=[N:56][CH:57]=2)=[CH:67][CH:66]=1
Reactant: O=C(O)c1ccc(-c2cncs2)cc1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-c2cncs2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 45.33 %

Procedure:
DIPEA (232 mg, 0.31 mL, 1.79 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (prepared by the method as described above) (190 mg, 0.54 mmol) in DMF (3 mL). HOBT (67 mg, 0.49 mmol) and EDCI (172 mg, 0.89 mmol) were then added at room temperature. After 2 minutes, 4-thiazol-5-yl-benzoic acid (100 mg, 0.49 mmol) (prepared by the method described above) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 70% EtOAc in Hexane as eluent) to afford 102 mg (45.33% yield) N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-4-thiazol-5-yl-benzamide. LCMS Purity: 97.53%. 1H NMR (CDCl3): δ 8.8 (s, 1H), 8.16 (s, 1H), 7.92-7.84 (d, 2H), 7.78-7.72 (d, 1H), 7.7-7.52 (m, 4H), 7.38-7.3 (d, 2H), 4.36-4.3 (m, 1H), 4.28-4.2 (m, 1H), 4.1-4.0 (d, 2H), 3.98-3.88 (m, 1H), 3.8-3.64 (m, 2H), 3.64-3.5 (d, 2H), 3.44-3.18 (t, 1H), 3.3-3.21 (bs, 2H).
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:13][C:14]#[N:15].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[C:1]1([C:7]2[N:8]=[N:9][N:10]([CH2:13][C:14]#[N:15])[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2nnn[nH]2)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCn1nnc(-c2ccccc2)n1

Procedure:
To 146 mg (1 mmol) of 5-phenyltetrazole and 75 mg (1 mmol) of chloroacetonitrile was added three mL of dimethyl formamide. The resulting solution was stirred, then 158 mg (1 mmol) of potassium carbonate was added and the mixture was further stirred at room temperature for 18 hours. Twenty-five mL of water was then added and the mixture was extracted twice with 25 mL of ethyl acetate. Evaporation of the extracts left the crude product, which was purified by silica gel chromatography, leaving an oil that was pure by NMR.
Reaction SMILES: [CH3:1][C:2]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)([CH:4]1[S:8][CH2:7][CH2:6][S:5]1)[CH3:3].[CH3:17][O:18]C(Cl)Cl.O>ClCl.C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:2]([CH:4]2[S:5][CH2:6][CH2:7][S:8]2)([CH3:1])[CH3:3])=[CH:10][C:11]=1[CH:17]=[O:18]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(C(C)(C)C2SCCS2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: ClCl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(C)(C)C2SCCS2)cc1C=O
Temperature: -60 °C
Reaction time: 0.05 h
Yield: 30.5 %

Procedure:
To a stirred solution of Compound 80 (0.254 g, 1 mmol) in dry CH2 Cl2 (5 ml) was added a solution of TiCl4 in CH2Cl2 (1M, 3 ml) with cooling (-60° C.). After 3 min., to this was added dichloromethyl methyl ether (0.46 g, 4 mmol) dropwise. The reaction mixture was stirred at same temperature for 1 hr. The mixture was poured into water and stirred at room temperature for 15 min. The organic layer was separated and the aqueous layer was extracted with Et2O (50 ml×2). The combined solution was washed with brine, dried (MgSO4) and concentrated in vacuo to give crude product. The crude product was purified by a column chromatography to give Compound 81 (86 mg) as an oil
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[CH:4]=[N:5][NH:6][CH:7]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]2[N:24]([CH3:25])[N:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)[N:14]=1.O>CC(N(C)C)=O>[CH3:25][N:24]1[C:20]([O:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([N:5]3[CH:4]=[C:3]([C:2]([F:9])([F:8])[F:1])[CH:7]=[N:6]3)[N:14]=2)=[CH:21][C:22]([C:26]([F:29])([F:27])[F:28])=[N:23]1
Reactant: Cn1nc(C(F)(F)F)cc1Oc1cccc(F)n1
Reactant: FC(F)(F)c1cn[nH]c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1Oc1cccc(-n2cc(C(F)(F)F)cn2)n1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
0.262 g of 4-trifluoromethylpyrazole is introduced under nitrogen in 7 ml of dimethylacetamide and at 0° C. 0.057 g of NaH is added. The mixture is allowed to come to RT over 30 min and then 0.5 g of 2-fluoro-6-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)pyridine is added and the mixture is heated at 140° C. for 7 h, cooled to RT and poured into water. The product is extracted twice with ethyl acetate/heptane (1:1), washed with water and saturated sodium chloride solution, dried over MgSO4 and concentrated. Chromatographic purification on silica gel gives 0.349 g of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-6-(4-trifluoromethylpyrazol-1-yl)pyridine as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.BrCC1OC(C(F)(F)F)=CC=1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]2)[C:22]1=[O:41].CC1(C)COC2=CC3OCC4(C=3C=C12)C1C(=CC=CC=1)NC4=O>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:33]4=[CH:34][C:35]5[O:39][CH2:38][O:37][C:36]=5[CH:40]=[C:32]4[O:31][CH2:30]3)[C:22]2=[O:41])=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: CC1(C)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: O=C1N(Cc2ccc(Cl)nc2)c2ccccc2C12COc1cc3c(cc12)OCO3

Procedure:
Following the procedure described in EXAMPLE 10.21, and making non-critical variations using 2-chloro-5-(chloromethyl)pyridine to replace 2-bromomethyl-5-(trifluoromethyl)furan, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,5-dimethyl-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, the title compound was obtained (69%): 1H NMR (300 MHz, CDCl3) δ 8.42 (d, 1H), 7.63 (dd, 1H), 7.34-7.14 (m, 3H), 7.05 (t, 1H), 6.77 (d, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 5.89-5.84 (m, 2H), 5.07-4.78 (m, 3H), 4.66 (d, 1H); MS (ES+) m/z 407.3 (M+1).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[C:27]([O-])([O-])=[O:28].[K+].[K+].C=O.CCOC(C)=O.CCO>C1COCC1>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][N:20]([CH2:27][OH:28])[C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Agent: C=O
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCN(CO)C4=O)c2nc1NC(C)(C)C
Temperature: 50 °C
Reaction time: 8 h
Yield: 2.8 %

Procedure:
A mixture of 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (193) (0.2 g, 0.57 mmol), K2CO3 (0.16 g, 1.14 mmol), and formaldehyde (Sigma-Aldrich) (0.46 mL of 37% wt. in water, 5.72 mmol) in THF (5.72 mL) were combined and stirred at 50° C. overnight. The reaction mixture was directly loaded onto a biotage and purified three times (0-100% EtOAc:EtOH (3:1)/hexane; 0-40% then 40% EtOAc:EtOH (3:1)/hexanes; then 0-20% then 20% EtOAc:EtOH (3:1)/hexanes) to yield the title compound (6 mg, 3% yield). 1H NMR (300 MHz, CDCl3) d ppm 1.49-1.75 (m, 23H) 2.56 (s, 3H) 2.95-3.10 (m, 2H) 3.20-3.34 (m, 1H) 3.74-3.91 (m, 2H) 4.79-4.92 (m, 1H) 4.98-5.08 (m, 2H) 7.01-7.14 (m, 1H) 7.31-7.46 (m, 1H) 7.59-7.72 (m, 1H) 7.89-8.03 (m, 1H) 12.51-12.65 (m, 1H). m/z (ES, +ve) 380.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[S:6][CH:5]=[C:4]([C:7]([OH:9])=O)[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH2:16].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O>CN(C=O)C.CCOC(C)=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][NH:16][C:7]([C:4]1[CH:3]=[C:2]([Br:1])[S:6][CH:5]=1)=[O:9]
Reactant: O=C(O)c1csc(Br)c1
Reactant: COc1cccc(CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(CNC(=O)c2csc(Br)c2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-Bromothiophene-3-carboxylic acid (70%) (200 mg, 0.6 mmol of monobromide) was dissolved in DMF with 3-methoxybenzyl amine (0.3 g, 2.2 mmol), EDCI (0.42 g, 2.2 mmol), and HOBt hydrate (0.06 g, 0.4 mmol). The reaction mixture was stirred at room temperature for 3 days, diluted with EtOAc and the organic layer washed with 10% citric acid, saturated sodium bicarbonate, and brine. The organic layer was then dried over sodium sulfate and concentrated to an oil, which was purified by column chromatography on silica (10 to 30 5 EtOAc/hexanes) to give the product as a colorless oil, 195 mg, 0.6 mmol, 100%. 1H NMR 500 MHz (CDCl3) 7.81 (1H, s), 7.35 (1H, s), 7.28 (1H, m), 6.93 (1H, m), 6.87 (2H, m), 6.23 (1H, br s), 4.57 (2H, d), 3.84 (3H, s).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([SH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][CH2:39][Cl:40])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:24]3[C:33]4[C:28](=[CH:29][C:30]([O:36][CH2:37][CH2:38][CH2:39][Cl:40])=[C:31]([O:34][CH3:35])[CH:32]=4)[N:27]=[CH:26][N:25]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(S)c2)no1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 85 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-mercapto-phenyl)-urea described in Example 44A (303.02 mg, 1.04 mmol) in THF:DMF (2:1, 6 mL) was added NaH (95%, 28.9 mg, 1.144 mmol), stirred for 5-10 min at ambient temperature. Then (4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline, (300 mg, 1.04 mmol) described in Example 27A was added as solution in DMF:THF (2:1). The reaction mixture was then stirred overnight. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and washed the ethyl acetate layer with water and brine successively. The organic layer was dried (Na2SO4) concentrated to dryness to afford the pure 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (480 mg, 85%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.68 (s, 1H), 7.85 (s, 1H), 7.60-7.28 (m, 5H), 6.50 (s, 1H), 4.35 (t, 2H), 4.05 (s, 3H), 3.82 (t, 2H), 1.30 (s, 9H); LC-MS (ESI) m/z 542 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[Br:16]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:16][CH2:8][C:5]1[N:4]=[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[C:2]([Cl:1])=[CH:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(-c2cccc(F)c2)n1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: Fc1cccc(-c2nc(CBr)ccc2Cl)c1
Temperature: 74 °C

Procedure:
To a solution of 3-chloro-2-(3-fluorophenyl)-6-methylpyridine (0.435 g, 2.0 mmol) in CCl4 (40 mL) was added N-bromosuccinimide (0.350 g, 2.0 mmol). The reaction mixture was heated to 74° C. and AIBN (0.027 g, 0.16 mmol) was added. The reaction mixture was heated to reflux for 1 d, diluted with EtOAc, washed with H2O (1×), brine (1×), dried over MgSO4, filtered through a pad of silica (1.5 cm), and concentrated. The product, 6-(bromomethyl)-3-chloro-2-(3-fluorophenyl)pyridine, was used without further purification.